While the early diagnosis of cancer has been fully respected, it is still however often difficult for clinicians to confirm malignant pleural effusions ( PE), which essentially indicate the end-stage cancer. It has now been demonstrated that vascular endothelial growth factor ( VEGF) is a pivotal angiogenesis factor and associated with tumor growth and metastasis. The aim of this study was then to assess the diagnostic performance of VEGF in malignant PE. In this controlled and blinded prospective study, 113 consecutive patients with PE were recruited. For each eligible case, the VEGF levels of pleural fluid (PF) and serum were examined simultaneously using enzyme immunoassay. The reference standard for malignant PE was clinical evaluation and PF cytology with pleural biopsy, other examination and follow-up added as needed. According to the final diagnoses, 81 qualified cases were grouped as malignant (n = 32) and benign (n = 49) PE. For PF VEGF level, the mean in malignant group was higher than that in benign group 1358 +/- 91493 pg/mL vs. 422 +/- 9317 pg/mL, p = 0.001). As did for serum VEGF level (650 +/- 9533 pg/mL vs. 137 +/- 189 pg/mL, p<0.001). Using receiver operating characteristic analysis, the determined diagnostic cut-off points of VEGF levels of PF and serum for malignant PE were 959.25 pg/mL and 212.36 pg/mL, with sensitivities of 47%, 69% and specificities of 96%, 88%, respectively. For cascade connection and parallel operation of PF VEGF and serum VEGF, the sensitivities were 34%, 81% at specificities of 98%, 86%, respectively. These findings suggest that VEGF could be used in diagnosing malignant PE as a useful adjunct of conventional algorithm. Different VEGF test strategies, including test on PF, serum and both, may be selected according to practical needs.